Under circumstances where the accumulated incidence rate and mortality of cancer keep on increasing, it is a challenge to detect cancer in its early stages at every site. If cancer is detected in its early stages, the risk of invasion during therapy can be reduced and it is also expected that the cancer can be cured completely. Protocols for early therapy have been established for each cancer, and hence there is a demand for simple techniques having high diagnostic ability. Moreover, in the case of a patient who has been diagnosed as having advanced cancer, accurately diagnosing the presence or absence of distant metastasis is very important for determination of the patient's disease stage and the therapeutic strategy required subsequently. Cancer therapies include surgical operations, radiotherapy and chemotherapy. In the case of surgical operations, it is expected that cancer can be cured completely when metastasis lesions are precisely excised or cauterized. Radiation therapy also allows reduction of side effects when tumor sites are precisely determined and selectively irradiated to thereby avoid irradiation in other normal sites. In these senses, accurate diagnosis of cancer sites is very advantageous for cancer patients at all stages of the disease.
Diagnostic imaging of malignant tumors is typically exemplified by X-ray CT imaging, ultrasonic echo imaging, and magnetic resonance imaging (MRI). These diagnoses are widely used and each have both advantages and disadvantages. Among them, MRI is advantageous in that it requires no exposure to radiation and is a highly objective and reproducible method. However, it has been difficult for MRI to identify small tumors by its hardware alone.
To compensate such a disadvantage, various contrast agents have been developed and practically used for enhancing contrast between tumor tissues and their surrounding tissues. Typical contrast agents include metal complexes such as Gd-DTPA (gadolinium-diethylene triamine pentaacetic acid), which has side effects such as hepatotoxicity and nephrotoxicity although Gd-DTPA is in a chelated form with reduced side effects compared to free Gd. Moreover, Gd-DTPA is not site-specific and is rapidly diffused into individual organs and muscle tissues upon intravenous injection. Thus, there has been a limit on the time required between administration and imaging, and it has also been necessary to administer a large amount of contrast agent to ensure clear contrast between tumors and non-tumor tissues.
For these reasons, there is a demand for the development of a contrast agent which accumulates in a tumor-specific manner, achieves high contrast even in a small amount, is safe with reduced side effects, and also has a long retention time in blood.
In tumor tissues, due to their properties different from those of normal tissues, e.g., neovascular outgrowth and highly enhanced permeability of vascular walls, as well as undeveloped lymphatic system, even high-molecular-weight substances can be transferred from blood to tumor tissues and are less likely to be excreted from the tissues once they have been transferred. It is therefore known that nano-size particles such as liposomes or polymeric micelles encapsulating various agents (e.g., anticancer agents) eventually accumulate in tumor tissues, as a result of the so-called EPR effect, which facilitates accumulation of high-molecular-weight compounds and/or nano-size particles in tumor tissues (see Patent Document 1).
On the other hand, polymeric micelles encapsulating a Gd complex in the core have been developed so far (see Patent Document 2). However, in these micelles, the Gd complex is directly attached and immobilized to a block copolymer constituting the micelles, as a result of which the relaxivity (contrast agent sensitivity) of Gd is suppressed and Gd is less likely to be excreted from tumor tissues. Thus, there has been a concern about problems of side effects such as hepatotoxicity and nephrotoxicity.